Original research
Tuberculous meningitis patient
To cite: Nijman G, Imran D,
Dian S, et al. Tuberculous
meningitis patient pathways
and delays to diagnosis in
Indonesia: a retrospective cohort
study. BMJ Public Health
2023;1:e000052. doi:10.1136/
bmjph-2023-000052
► Additional supplemental
material is published online only.
To view, please visit the journal diagnostic capacity for TBM at hospitals that had been
online (http://​dx.​doi.​org/​10.​
1136/​bmjph-​2023-​000052).
GN and DI contributed equally.
Received 14 March 2023
Accepted 18 October 2023
© Author(s) (or their
employer(s)) 2023. Re-­use
permitted under CC BY-­NC.
Published by BMJ.
For numbered affiliations see
end of article.
Correspondence to
Gerine Nijman;
​gerine.​nijman@​radboudumc.​nl
pathways and delays to diagnosis in
Indonesia: a retrospective cohort study
Gerine Nijman ‍ ‍ ,1 Darma Imran,2 Sofiati Dian,3 Ahmad Rizal Ganiem,3
Riwanti Estiasari,2 Kartika Maharani,2 Raesa Yolanda,2 Mimin Supriatin,3
Bachti Alisjahbana,4 Bony Wiem Lestari,4 Raph L Hamers,5,6 Philip C Hill,7
Reinout van Crevel1,6
ABSTRACT
Introduction Delays in diagnosis and treatment contribute
to high mortality of tuberculous meningitis (TBM). We
studied TBM patient pathways including delays to
diagnosis, and their alignment with available diagnostic
services in Indonesia.
Methods We recruited patients admitted to two tertiary
hospitals who started TBM treatment. Participants or
their relatives were interviewed to recall healthcare visits
preceding TBM treatment. We also surveyed available
visited by at least two patients preceding their study
enrolment.
Results Of 175 participants (median age 31 years, 57.1%
men), 85.1% had reduced consciousness or coma, and
46.9% had motor deficits including hemiparesis. Patients
attended a first healthcare provider, most often private
clinics (38.3%) or informal healthcare providers (22.3%),
at a median 14 days (IQR 1–34) after symptom onset.
They visited multiple providers (median 5, IQR 3–8) over
a prolonged time period (median 31 days, IQR 10–79)
preceding TBM diagnosis. Of 40 surveyed hospitals, 52.5%
could not or not always perform lumbar puncture, 22.5%
lacked cerebral imaging facilities and 31.6% and 84.2%,
respectively, could not provide routine microscopy or
GeneXpert MTB/RIF on cerebrospinal fluid.
Conclusion In these urban settings in Indonesia,
pathways to TBM diagnosis are complex and lengthy,
and patients often visit healthcare providers with limited
capacity to diagnose TBM. There is an urgent need for
interventions to strengthen health literacy and diagnostic
and referral processes in public and private health sectors
for complex patient groups like TBM.
INTRODUCTION
Tuberculous meningitis (TBM) is the most
devastating manifestation of tuberculosis
(TB). It is one of the most common causes
of brain infections, with an estimated 164 000
adult incident TBM cases globally in 2019.1
Based on this study and the Global TB report
2022, we estimate that there were at least 13
400 incident TBM cases in Indonesia in 2021,
Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052
BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒ In Indonesia, as in many other parts of the world,
tuberculous meningitis (TBM) has a very high mor-
bidity and mortality. Studies have mainly focused on
clinical characteristics, diagnosis and antibiotic or
copyright.
immunomodulatory treatment, but not on patients’
access to healthcare.
WHAT THIS STUDY ADDS
⇒ Patients with TBM experience complex and lengthy
pathways before TBM is diagnosed, mostly at an ad-
vanced stage. Diagnostic capacity for TBM and other
brain infections is very limited outside top-­referral
hospitals.
HOW THIS STUDY MIGHT AFFECT RESEARCH,
PRACTICE OR POLICY
⇒ In a country like Indonesia, public health interven-
tions to improve patients’ access to high-­quality
healthcare services will be crucial for improving out-
comes of TBM and other brain infections.
which is 8% of the global estimate. In a recent
Indonesian cohort among 793 patients with
central nervous system infections, 44% were
caused by Mycobacterium tuberculosis (Maha-
rani, unpublished). TBM is fatal if untreated,
but even with treatment, patients have an esti-
mated mortality of 23–25% globally and up to
67% in studies from Asia,2 with at least one-­
third of survivors suffering from neurological
sequelae.2
Efforts to improve outcomes of patients
with TBM have mainly focused on improving
sensitivity of diagnostic tests and optimising
antimicrobial or adjuvant therapy. However,
few studies have addressed whether patients
with suspected TBM have access to high-­
quality diagnostic and therapeutic services
in a timely manner, and what barriers they
may experience in this regard. Delays in TBM
diagnosis and treatment have been reported
 1
BMJ Public Health
from different countries, and have shown strong associ-
ations with mortality.3 Accelerating diagnosis and treat-
ment is therefore a key objective in improving patient
outcomes for TBM. To do so, more insight is needed into
‘patient pathways’, concerning where and when patients
with TBM seek care prior to diagnosis, and whether the
right diagnostic services are available, and in such a
way that patients’ needs and preferences are met.4 For
pulmonary TB, previous studies have described patient
pathways and their alignment with diagnostic services.5 6
However, patient pathways for TBM are likely different as
TBM is more rare, more rapidly progressive and severe
at later stages, but most importantly much more difficult
to diagnose, due to its initial non-­specific symptoms, and
the need for lumbar puncture, cerebral imaging and
more advanced microbiological tests, none of which are
sufficiently sensitive.7 Better understanding of individual-­
level TBM patient pathways could therefore help to
identify barriers to diagnosis and improve allocation of
resources to areas where they are needed most.
Therefore, the aim of this study was first to charac-
terise TBM patients’ pathways, including delays, prior
to hospital admission in two tertiary hospitals in Indo-
nesia, which has the second highest number of TB
cases worldwide, and a broad range of health system
challenges, including a complex network of public and
private healthcare providers. Second, for the first time
we aligned patient trajectories with the availability of
TBM-­related diagnostic services using facility-­level data.
Findings in this study about TBM may share features with
patient pathways for other severe diseases in high-­burden
settings, and could provide insights into how to improve
efficiencies in the delivery of wider healthcare services.
METHODS
Study setting
This retrospective cohort study was conducted from
January 2020 to May 2022 in Cipto Mangunkusumo
hospital (RSCM) in Jakarta and in Hasan Sadikin hospital
(RSHS) in Bandung. Both hospitals are government-­
owned university hospitals and serve as sole tertiary
referral centres for brain infections in Jakarta (~11
million inhabitants) and West Java province (~50 million
inhabitants). Indonesia’s public healthcare system is
decentralised, and the district level government has
the main responsibility for provision and management
of healthcare service in city hospitals and primary care
centres (pusat kesehatan masyarakat or ‘Puskesmas’). Also,
the private sector plays an important role in healthcare
provision in Indonesia, with ~63% of hospitals managed
by the private sector in 2021,8 and a large number of
private primary care providers. Many Indonesian patients
seek care in private sector facilities or at informal care
providers, such as drug stores, traditional spiritual healers
or alternative practitioners.6 9 To achieve universal health
coverage, the government launched Jaminan Kesehatan
Nasional in 2014, Indonesia’s mandatory social health
2 Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052
insurance scheme. By 2021 it covered 86% of the popu-
BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
lation, and included almost all public hospitals, the
majority of Puskesmas and private hospitals, but only a
limited number of private clinics.8
Study population
Patients were included in the study if they were ≥18
years old, admitted to the emergency room or neurolog-
ical ward in one of the two study hospitals, and started
on TBM treatment for a presumed diagnosis of TBM.
Patients were excluded if they (or their relative for
patients that were not fully conscious or had cognitive
impairment) did not provide written informed consent,
if they returned to the hospital with sequelae of previous
episodes of TBM (e.g. seizure) without current TBM, if
the patients or their relatives could not be contacted, if
patients died or went home before recruitment, or if they
were discharged with a diagnosis other than TBM.
Procedures and definitions
Patients were interviewed in their native language using
a structured questionnaire (online supplemental mate-
copyright.
rial 1). The questionnaire was developed based on the
‘Tool to estimate patients’ cost’ from the Dutch Tubercu-
losis Foundation (KNCV TB Foundation), and adapted
to TBM and the Indonesian context through rounds
of discussion with experts and through pilot testing. If
patients were not fully conscious or had cognitive impair-
ment, close relatives accompanying the patients in the
hospital and familiar with their medical history were
interviewed instead. The interviewee was asked to recall
in chronological order the dates of onset of symptoms
and subsequent visits to healthcare providers until inclu-
sion in the tertiary study hospitals. If patients could not
remember exact dates, they were asked to relate their
experiences to memorable events, such as Islamic Eid
al-­Fitr. Subsequently, the first day of the week, month or
year that the interviewee was able to recall was recorded.
Symptoms were categorised as neurological and
general. Neurological symptoms included altered
consciousness, headache, behavioural changes, vomiting
(often occurring as a result of raised intracranial pres-
sure), motor and sensory abnormalities, cranial nerve
palsy, seizures and other symptoms mentioned by patients,
such as visual impairment or vertigo. General symptoms
included fever, lethargy, weight loss, night sweats, cough,
haemoptysis and other symptoms mentioned by patients,
such as gastrointestinal symptoms and lumps in the neck.
Subsequently, for each healthcare visit, the interviewee
was asked to recall the type of healthcare provider, reasons
for visiting that provider, tests performed, potential diag-
noses made and the treatment provided. Provider types
were defined based on Hanson et al,4 and adapted to the
Indonesian context (table 1).9
Dates of hospital admission, diagnosis and treatment
initiation were verified using patients’ medical records.
Date of diagnosis was defined as the day of presump-
tive or confirmed diagnosis of TBM (whichever came
 BMJ Public Health

BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
Table 1 Definitions of healthcare providers and their diagnostic and treatment capacity
Type of healthcare provider Definition and capacity for diagnosis and treatment
Services for basic care (e.g. pharmacies and drug stores), practitioners without formal
medical training (e.g. shaman, alternative doctors, traditional massages, clerics) or
practitioners not formally allowed to prescribe TB medication (e.g. midwives). No TB(M)
diagnostics available. TB treatment is generally not available, although sometimes distributed
Informal care provider without prescription.
Private facilities that provide primary healthcare, generally on an outpatient basis. TB(M)
Private clinic diagnostics largely unavailable, but TB treatment may be available.
Government-­owned facilities that provide primary healthcare, generally on an outpatient basis
(‘puskesmas’). Smear microscopy and TB treatment are largely available, but availability of
GeneXpert MTB/RIF is limited. Neurological diagnostic services (i.e. LP, cerebral imaging and
Primary health centre CSF analysis) are generally unavailable.
Private facilities that provide secondary level outpatient and inpatient healthcare. In general,
they provide more neurological diagnostic services and TB treatment compared with primary
Private hospital healthcare providers. Availability of GeneXpert MTB/RIF is limited.
Government-­owned facilities that provide secondary level health outpatient and inpatient
care. In general, they provide more TB and neurological diagnostic services and TB treatment
Public hospital compared with primary healthcare providers. GeneXpert MTB/RIF is sometimes available.
Government-­owned specialised healthcare facilities with large inpatient capacity and
specialised doctors. TB and neurological diagnostic services and TB treatment largely

copyright.
Tertiary hospital available.
CSF, cerebrospinal fluid; LP, lumbar puncture; TB, tuberculosis; TBM, tuberculous meningitis.

first) by an experienced team of senior neurologists in
both sites, based on clinical assessment, cerebrospinal
fluid analysis and/or cerebral imaging. As Indonesian
guidelines recommend identical treatment regimens for
pulmonary and meningitis TB, date of treatment initia-
tion was defined as the day in which anti-­TB drugs for
either pulmonary TB or TBM were initiated. Treatment
initiated for pulmonary TB but interrupted or completed
before TBM diagnosis was considered ‘history of TB treat-
ment’, and not considered in the date of TBM treatment
initiation. If patients explicitly reported that doctors
mentioned a TBM diagnosis and/or started anti-­TB treat-
ment during a previous visit in their trajectory, this was
considered the date of diagnosis or treatment, respec-
tively, and was checked in the medical records.
Time delays were summarised based on World Health
Organization (WHO) definitions10: patient delay was
defined as the number of days between onset of symptoms
and the patient’s first visit to any healthcare provider;
diagnostic delay was defined as the number of days from
symptom onset to TBM diagnosis; and treatment delay as
the number of days between TBM diagnosis and initia-
tion of anti-­TB drugs.
To evaluate how patient pathways align with diag-
nostic services in the healthcare system, hospitals that
were visited by two or more patients prior to their study
enrolment were assessed. Through an online survey or
a phone interview, we asked neurologists employed in
these hospitals to provide information about availability
of TBM-­related diagnostic resources, that is, the number
of neurologists, lumbar puncture equipment, cerebral
imaging and laboratory analyses on cerebrospinal fluid
(online supplemental material 2). For hospitals without a
neurologist, we consulted the hospital’s website or other
physicians or administrators employed in the concerning
hospital. Information about the hospital’s type and
size was retrieved from the online hospital information
dashboard.11
Analysis
We performed descriptive analyses to summarise data on
patient pathways and delays. Furthermore, the type of
providers visited by patients over sequential healthcare
visits are presented in a bar graph. We also visualised
the type of providers visited by patients over time since
symptom onset in a bar graph. If patients visited multiple
healthcare providers in a single time frame, we selected
the highest-­level provider for that time frame according
to table 1. The association between HIV status and diag-
nostic delay was evaluated using the Mann-­Whitney U
test, and the effect of diagnostic delay on the British
Medical Research Council (MRC) grade at recruitment
was assessed with ordinal logistic regression.
Ethical considerations
Patients or their family members, if the patient was not
fully conscious or had cognitive impairment, provided
written informed consent prior to study enrolment.
Patient and public involvement
To our knowledge, this is one of very few studies within
the TBM field that is guided by patient’s perspectives and
that highlights their experiences and challenges. During

Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052 3

BMJ Public Health

pilot-­testing of the questionnaire, participants provided

BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
Table 2 Patient characteristics
feedback about the burden and time to participate.
Total (n=175)
Age, median (IQR) 31 (24–46)
Sex, male 57.1
RESULTS
From January 2020 to May 2022, 175 patients with TBM Socioeconomic information
were included; 99 from the study hospital in Jakarta and  Marital status
76 from Bandung (online supplemental material 3). A   
Married 50.3
close relative accompanying the patient was interviewed   
Single 37.7
for 114 (65.1%) patients with reduced consciousness.
  
Widowed 5.7
Patients were generally young, with a median age of
31 years (IQR 24–46), and 57.1% were man (table 2).   
Divorced 6.3
Furthermore, 58.3% had other forms of TB besides TBM  Primary income earner of the household,
at the time of admission, mostly pulmonary TB. Patients patient with TBM 42.3
presented with severe signs and symptoms, including  Highest education level
reduced consciousness (85.1%), motor abnormalities   Secondary school or lower 32.0
(46.9%) and a history of seizures (25.7%), as well as   High school completed 47.4
frequent headache (84.0%), fatigue (78.9%) and fever
  College or higher education 20.6
(74.9%). Most patients (91.4%) self-­reported that this
resulted in difficulty with their daily activities. Most  Normal work situation
patients were diagnosed with advanced disease, TBM   Full-­time or part-­time work for pay 55.4

copyright.
grade II (79.1%) or III (16.9%).   Unemployed/looking for work 18.9
  
Housewife/husband 13.7
Patient pathways and delays   Student at school or university 5.7
Patient pathways to diagnosis were characterised by
  
Retired 2.3
numerous healthcare visits to different providers and
long delays. The median time between symptom onset   
Other 4.0
and patients’ first encounter with a healthcare provider,  Insurance
that is, patient delay, was 14 days (IQR 1–34). Patients   
Government insurance 92.0
mostly visited private clinics (34.7%), informal care   
Private insurance 1.1
providers (21.2%) and community health centres
  Government and private insurance 3.4
(12.4%) after onset of general symptoms, mainly because
of proximity to their home or easy accessibility (36.6%),   
No insurance 3.4
and familiarity with the provider (14.9%). After neuro- Comorbidities
logical symptoms, patients mostly initially visited private  HIV (n=169) 23.1
clinics (30.3%), tertiary referral hospitals (17.1%) and  Diabetes (n=172) 5.8
informal care providers (16.6%). Patients had a median
 History of TB treatment (n=163) 27.6
of 5 healthcare visits (IQR 3–8), with a range of 1–24
visits, preceding TBM diagnosis (figure 1A). The time  Other current forms of TB 58.3
from first healthcare visit to TBM diagnosis was median   
Pulmonary TB 54.3
31 days (IQR 10–79). The median diagnostic delay, that   
TB lymphadenitis/lymphadenopathy 5.7
is, time from symptom onset to TBM diagnosis, was 66   
TB spondylitis 2.3
days (IQR 31–128) (figure 1B); 74 days (IQR 32–172) in
  
Abdominal/peritoneal TB 1.7
Jakarta and 61 days (IQR 29–97) in Bandung, possibly
due to difference in case mix. For those with other forms   
TB arthritis 0.6
of TB (58.3%), time from general symptoms to neurolog-   
Uterine TB 0.6
ical symptoms was 20 days (IQR 0–74) and time to TBM Symptoms
diagnosis was 65 days (IQR 31–128). HIV positive patients  Neurological symptoms
did not have significantly different median patient delay
  
Altered consciousness 85.1
compared with HIV negative patients (23 days (IQR
6–39) vs 14 days (IQR 1–33), p=0.12), which was similar   
Headache 84.0
for time from first healthcare visit to TBM diagnosis (32   
Behavioural change 61.7
days (IQR 14–89) vs 31 days (IQR 9–73), p=0.45). With   
Vomiting 49.7
every 10 days increase in diagnostic delay, the likelihood   Motor abnormalities 46.9
of a higher MRC grade at recruitment increased with 3%
  Cranial nerve palsy 37.1
(OR 1.03, 95% CI 1.00 to 1.05). Finally, the median treat-
ment delay was 1 day (IQR 0–1). Continued

4 Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052

 BMJ Public Health

form of TB prior to TBM diagnosis (figure 2, pathway 1).

BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
Table 2 Continued
Many of them (66.7%, n=78) only started seeking care
Total (n=175) after onset of neurological symptoms, with a median of
  
Seizure 25.7 5 visits (IQR 2–6) over 23 days (IQR 7–60) until a TBM
  
Sensory abnormalities 12.0 diagnosis was made. They most frequently visited private
clinics (37.6%) and informal care providers (23.1%)
  Other neurological symptoms* 11.4
after general symptoms, and private clinics (26.5%)
 General symptoms and tertiary referral hospitals (20.5%) after neurolog-
  
Lethargy 78.9 ical symptoms. In an alternative scenario, some patients
  
Fever 74.9 recorded first having neurological symptoms (figure 2,
  
Weight loss 62.9 pathway 2), followed by more general symptoms after a
median of 38 days (IQR 29–90) for 13 patients (72.2%).
  
Cough 33.7
Patients with this scenario needed a median of 6 visits
  
Night sweats 30.3 (IQR 4–7) over 58 days (IQR 15–96) prior to TBM diag-
  
Coughing blood 5.7 nosis. They most often visited private clinics (38.9%),
  Other general symptoms† 25.1 informal care providers (16.7%) and community health
 Chief complaint‡
centres (16.7%) after neurological symptoms, and
private hospitals (61.5%) and public secondary hospi-
  
Altered consciousness 60.0
tals (15.4%) after subsequent general symptoms. Finally,
  
Seizure 14.3 some patients (22.9%, n=40) were first diagnosed with
  
Headache 11.4 another form of TB, a median of 45 days (IQR 27–145)
Self-­reported socioeconomic impact of after onset of general symptoms and 31 days (IQR 15–51)

copyright.
TBM prior to diagnosis prior to TBM diagnosis (figure 2, pathway 3–8). Of those,
 Unable to do daily activities 91.4 23 started TB treatment a median of 24 days (IQR 15–42)
prior to TBM diagnosis (figure 2, pathway 3, 5, 7). There
 Stopped work/housework/school 84.6
was no clear relation between particular pathway groups
 Stopped socialising with family/friends 21.7 and disease severity at time of recruitment. In the first
 Affected self-­esteem 8.0 group, 4.3% had MRC grade 1 at recruitment, 76.7%
Admission to tertiary study hospital grade 2 and 19.0% grade 3, and for the second group
 GCS at admission (n=170), median (IQR) 13 (11–15) 0.0%, 83.3% and 16.7%, respectively. Individual patient
pathways are presented in online supplemental material
 TBM grade at admission (n=172)
4.
  
I 4.1
  
II 79.1 Barriers to diagnosis
  
III 16.9 From patients’ narratives of the four most common
 Time from admission to neurologist team pathways, some challenges that caused diagnostic delays
in hours (n=167), median (IQR) 2.6 (0.3–9.4) were identified (panel 1). For instance, involvement of
 LP done (n=174), yes 90.8
informal and private care providers likely led to signifi-
cant delays. This is shown by the fact that median time
 For those with LP done: time from
from first healthcare visit to TBM diagnosis was signifi-
admission to LP in hours, median (IQR) 34.3 (15.2–70.8)
cantly longer for those who initially visited informal or
 In-­hospital mortality 22.3 private providers compared with those who initially visited
Data are presented as percentages, but age, GCS score and time public community health centres and public secondary
variables are presented as medians including IQR. level hospitals (39 days (IQR 14–89) vs 24 days (IQR
*Other neurological symptoms were for instance blurry or double 10–58), p=0.04). Moreover, doctors often suspected alter-
vision, vertigo, hearing impairment and cognitive problems.
native diagnoses, such as typhoid fever (n=30), gastritis
†Other general symptoms consisted of for instance dyspnoea,
loss of appetite, lumps in the neck and gastrointestinal problems. (n=17), ‘regular headache’ (n=14) or stroke (n=14). In
‡These were the three most frequently reported chief complaints. six patients, traditional or spiritual healers falsely diag-
Other chief complaints were behavioural change (n=6), cranial nosed them as having a curse or disturbance of spirits.
nerve palsy (n=5), motor abnormalities (n=4), lethargy (n=3), fever
(n=2), weight loss (n=1) or other symptoms (n=4).
Alignment of patient pathways with availability of TBM
GCS, Glasgow coma scale; LP, lumbar puncture; TB, tuberculosis;
TBM, tuberculous meningitis. diagnostic services
Of 49 hospitals that were visited by two or more patients
prior to enrolment, 40 (81.6%) provided information
Patients’ pathways were variable, but many patients had about availability of TBM-­related diagnostic capacity and
a similar sequence of events (figure 2). Most patients devel- services (online supplemental material 5). Even though
oped neurological symptoms about 2 weeks after onset of most hospitals (92.5%) had a neurologist, 52.5% did not
general symptoms, without getting a diagnosis of another always have access to supplies for lumbar puncture, and

Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052 5

BMJ Public Health

BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
copyright.
Figure 1 Type of healthcare providers and visits made before TBM diagnosis. The types of healthcare providers visited prior
to diagnosis, with the cumulative proportion diagnosed with TBM in green. In (A) the x-­axis indicates the number of sequential
healthcare visits leading up to a diagnosis, and the y-­axis indicates the proportion of patients with TBM that visit different types
of healthcare providers in the concerning visit. In (B) the x-­axis indicates the time after onset of first symptoms, regardless of
general or neurological nature. The different colours distributed over the y-­axis indicate the highest level of provider visited by
patients during that time frame, according to the order in table 1. = has not sought care yet, = has visited a healthcare
provider in a previous time frame, but not in this time frame, = visited an informal provider but not diagnosed yet, = visited
a private clinic but not diagnosed yet, = visited a community health centre but not diagnosed yet, = visited a private
secondary level hospital but not diagnosed yet, = visited a public secondary level hospital but not diagnosed yet, = visited
a public tertiary level hospital but not diagnosed yet, = diagnosed in a private secondary level hospital, = diagnosed in a
public secondary level hospital, = diagnosed in a public tertiary level hospital. TBM, tuberculous meningitis.

22.5% lacked cerebral imaging. Finally, many had no
facilities for routine cerebrospinal fluid analysis (31.6%),
cerebrospinal fluid smear microscopy (47.4%), GeneX-
pert MTB/RIF (84.2%), or TB culture (65.8%).
DISCUSSION
In this study, we found that patients, almost all of whom
were young, had experienced complex, variable and
lengthy pathways before TBM was diagnosed, mostly
at an advanced stage. Moreover, patients often visited
healthcare providers with limited capacity to diagnose
TBM. It took on average two weeks for patients to seek
care for their symptoms, and on average five healthcare
visits over about a month’s time until a diagnosis of TBM
was made. Especially in the early stages of the diagnostic
pathway, patients visited informal and private healthcare
providers, which typically lack the necessary diagnostic
capacity for TB or for brain infections. Similarly, hospi-
tals visited by patients with TBM often lacked capacity for
diagnosis of brain infections, such as cerebral imaging,
lumbar puncture facilities and cerebrospinal fluid anal-
ysis.
There are several possible reasons for delay in TBM
patients’ pathways to diagnosis. First, patients may
not (immediately) seek care after onset of symptoms.
Patient delays reported in our study were shorter than
reported for pulmonary TB in the same setting in Indo-
nesia,6 likely because TBM symptoms can be more severe.
Comparable to our study, studies from Taiwan and China
reported a median time of 1–4 weeks from onset of TBM
symptoms to presentation to a tertiary hospital.12–14 Care-­
seeking of patients with TB may be hindered by patient-­
related barriers, such as limited knowledge about TB,
gradual onset of symptoms, stigma associated with the
disease, attribution of symptoms to other causes (e.g.
HIV), negative perceptions and attitudes towards health-
care providers, and health-­system related factors such as
geographical and financial barriers to access care.15–17
Second, patients who do seek care for their symptoms,
may not go to caregivers or facilities that have the clin-
ical knowledge, experience and capacity to diagnose and
treat TBM. In our study, the majority of patients with TBM
first went to an informal provider or private clinic, similar
to pulmonary patients with TB in Indonesia.5 6 9 These
entry-­points have a key role in timely diagnostic-­workup

6 Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052


Figure 2 Sequence of events for subgroups of patients with TBM. The different orders of events for subgroups of patients
with TBM with regards to symptoms, diagnosis of TBM and other forms of TB, as well as TB treatment. TB regimens that were
initiated because of other forms of TB, but that were discontinued prior to TBM diagnosis are not considered in this graph as
TB treatment. TB, tuberculosis; TBM, tuberculous meningitis.
and efficient referral but are also characterised by
provider-­ related barriers. For instance, in high TB
burden counties like Indonesia and India, informal and
private providers, especially in outpatient primary care
but also in high-­end specialised hospitals, are known to
largely lack or underutilize diagnostic services for TB,
to not treat TB according to local guidelines, to poorly
refer to national TB programmes and to have large gaps
between knowledge and practice.18
Third, those who eventually reach higher level, special-
ised hospitals still experience complex and lengthy path-
ways to diagnosis and treatment. Studies from China,
India, South Africa and Taiwan have reported delay
between 9 days to 6 weeks from TBM symptom onset to
treatment initiation.12 19–21 Furthermore, studies from
China, India and South Africa have reported a median
2.4 to 4 healthcare visits preceding TBM diagnosis,19 21 22
and a mean 1.7 hospitalisations and 4.7 outpatient clinic
visits prior to treatment initiation.14 Health system delays
in TBM are clearly universal, and caused by challenges
both from demand side, that is, the patient, and from
the supply side, that is, the health system. Health-­system
barriers to pulmonary TB diagnosis and treatment besides
previously mentioned factors are for instance scarcity of
Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052
BMJ Public Health
BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
copyright.
trained doctors, lack of laboratory facilities, shortages
in TB medication and catastrophic household costs for
care.15 16 For TBM these are further complicated by atyp-
ical symptom presentation, low sensitivity of diagnostic
tests, hesitancy among clinicians to perform lumbar
puncture, limited availability of diagnostic resources and
inadequate TBM treatment regimens.7 17 23 Limited avail-
ability of diagnostic resources in hospitals reported in
our study was consistent with reports from a recent large
survey, where 73.3% of African inhabitants had access
to routine lumbar puncture services, but often only in
teaching hospitals and not regional or local hospitals.24
Although Indonesia has made significant progress in
moving towards universal health coverage,25 the find-
ings of this paper call for further strengthening of care
cascades for patients with complex diseases like TBM.
This requires further investments in all levels of the
healthcare system, including both the public and the
private sector, to achieve strong patient-­centred care with
universally accessible, high-­ quality and equitable diag-
nostic and therapeutic health services. Although further
research should be aimed at systematically identifying
and addressing modifiable factors related to patients,
healthcare providers and the wider health system, we can
7
BMJ Public Health

BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
PANEL 1 PATIENTS’ NARRATIVES OF THEIR PATHWAYS UNTIL TUBERCULOUS MENINGITIS (TBM) DIAGNOSIS

PATHWAY 1: INVOLVEMENT OF MIDWIFE AND CLERIC

A 19-­year-­old pregnant woman with no comorbidities and no history of tuberculosis (TB) developed a headache, dizziness and lethargy. Four times
she went for regular check-­ups to her midwife, who attributed her symptoms to pregnancy. After 2.5 months, the midwife referred the patient to
a private hospital, where she was admitted and diagnosed with a urinary tract infection. Two weeks later, the patient had fever, vomiting, altered
consciousness and behavioural changes for which she visited a religious healer twice, because she thought her symptoms were due to supernatural
causes. The religious healer diagnosed the patient as having a ‘trance’. Two weeks later, the patient visited her midwife again for a check-­up, who
now referred her to a different private hospital, leading to a diagnosis of typhoid fever and antibiotic treatment. Eventually, 3.5 months after onset
of initial symptoms, the patient developed motor abnormalities and cranial nerve palsy and presented to the emergency room of the tertiary referral
hospital the next day, where she was diagnosed with TBM and commenced on treatment.

PATHWAY 2: PROLONGED PATIENT DELAY AND OPHTHALMOLOGY

A 31-­year-­old HIV-­positive man without a history of TB initially developed visual impairment. Around a month later, the patient bought eye drops at a
pharmacy, but after a while he also had a persistent headache. Three months after his initial symptoms the patient visited a general practitioner at a
private clinic, who referred him to an ear-­nose-­throat specialist in a private hospital. A diagnosis of sinusitis was made, and the patient was treated
with antibiotics. The following 2 weeks, the patient twice visited a private ophthalmologist, who diagnosed the patient with optic nerve damage.
A few days later, the patient also started vomiting and became lethargic, and visited two private hospitals that suspected the patient of glaucoma
and papilloedema. Again a week later, the patient had reduced consciousness, behavioural changes and cranial nerve palsy. A general government
hospital referred him immediately to an ophthalmologist in the tertiary referral hospital, who suspected a brain tumour and referred the patient to the
neurology department, where he was diagnosed with TBM and commenced on treatment.

PATHWAY 3: TBM DESPITE ONGOING PULMONARY TB TREATMENT

copyright.
A 24-­year-­old woman without any comorbidities or history of TB developed a fever, cough and night sweats. In the following 2 weeks, she twice
visited a pharmacy to buy vitamins. About 2.5 months later, she also developed a headache, vomiting and a seizure, so she twice visited a private
general practitioner, who diagnosed her with dyspepsia and dehydration. The general practitioner at the private clinic referred her to a private hospital
where the patient was admitted, diagnosed with pulmonary TB and treated for 14 days. However, in the following week, despite TB treatment, she
developed altered consciousness, behavioural changes, cranial nerve palsy and motor abnormalities. She again visited the private hospital, which
referred her to the emergency ward of the tertiary referral hospital, where she was diagnosed with TBM and started on optimal treatment.

PATHWAY 4: DYSPEPSIA AND DISCONTINUED TB TREATMENT

A 24-­year-­old man without comorbidities or a history of TB developed weight loss, cough and a headache. In 2 months the patient visited four drug
stores and three different private clinics, where his symptoms were attributed to typhoid fever and dyspepsia. Two months after onset of the initial
symptoms, the patient also developed lethargy, fever and behavioural changes. A primary healthcare clinic referred him to a secondary government
hospital and subsequently a tertiary hospital for diagnosis. There, the patient was admitted, diagnosed with pulmonary TB and treated for 7 days. The
patient discontinued his treatment, and twice visited a private clinic where dyspepsia was suspected and treated accordingly. Around 1.5 month later,
the patient developed altered consciousness, haemoptysis and vomiting, for which he visited a secondary public hospital. The doctors suspected TBM,
and referred him to the tertiary referral hospital, where this was confirmed, and appropriate treatment was started immediately.

make some preliminary recommendations based on the
findings of this study. First, community-­based interven-
tions could be aimed at improving health literacy. Health
literacy interventions have been shown to promote
awareness and knowledge about particular health-­related
issues, and to enhance patients’ ability to find, understand
and use information and healthcare services,26 which
could reduce patient delays.27 Second, at the provider-­
level, interventions could focus on encouraging and facil-
itating prompt use of lumbar puncture,23 28 which has
been associated with reduced mortality in acute bacterial
meningitis,28 and better triage of TB and brain infections
at lower level public and private healthcare facilities,29
including timely notification and referral. Finally, health-­
system wide efforts should be aimed at further engaging
the private sector in provision of TB care,29 30 decentral-
ising TB diagnostic services29 and increasing efficiency of
referral processes. Some of the issues raised in this paper
are likely to be similar across different settings, such as
mild symptom onset or difficulty with recognising symp-
toms as TBM. However, the structure and organisation
of the health system, resource capacity and sociocultural
context, that also greatly influence patient pathways, can
vary substantially between settings.
This is the largest study to examine diagnostic
pathways for TBM. In one of the most populous parts
of Indonesia and for the first time, we also aligned
TBM pathways with diagnostic services of 40 hospitals
visited by patients prior to diagnosis. There are some
study limitations. First, because of the study design
we could not include patients who did not access
a tertiary hospital or who were never diagnosed,
including those who died prior to diagnosis. This
may have resulted in recruitment bias towards more
severe presentation of TBM, although severe TBM
may also be present but under-­r ecognised, underdi-
agnosed or die at other facilities (such as informal
or private healthcare providers). In our study, those
with longer diagnostic delays had more severe
disease at time of recruitment. However, we do not
have data about disease severity or course during the
patient pathway and its effect on recognition of TBM

8 Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052


by health providers, or on delays. Those with mild
presentation may be harder to recognise as possible
central nervous system infection, and lumbar punc-
ture is performed infrequently 23 especially for those
with mild disease. Patients experiencing long delays
and complex diagnostic pathways in our study may
serve as a proxy and could help to understand path-
ways of those who are not appropriately diagnosed
with TBM. Second, diagnostic pathways in this study
were assessed using patients’ and families’ recall,
noting that it is difficult to determine the exact time
of onset of TBM. TB and TBM symptoms can have an
insidious start, which can form difficulty in exactly
remembering dates of symptom onset. Although we
asked patients to relate their experiences to memo-
rable events, some recall bias likely exists. Finally,
healthcare may have been affected by surges of
COVID-­1 9 infections during the study period. Hospi-
tals were frequently overburdened, with limited
human and material resources, and TB symptoms
may have been attributed to COVID-­1 9, which may
have caused further delays. 31
CONCLUSION
In conclusion, pathways of patients with TBM in this
high-­b urden setting in Indonesia are complex and
lengthy and patients often visit healthcare providers
with limited diagnostic capacity for TBM. This high-
lights the need to look beyond improving diagnostic
tests and therapeutic strategies for TBM, and to
improve care continuity for complex diseases like
brain infections, for instance, by improving health
literacy in the community, further decentralisation
of diagnostic services and strengthening of referral
processes including guidelines and insurance regu-
lations, in both the public and private sector. This
should shorten patient’s journeys and increase the
proportion of patients receiving appropriate treat-
ment in time, and surviving this most deadly mani-
festation of TB.
Author affiliations
1
Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI),
Radboudumc, Nijmegen, The Netherlands
2
Department of Neurology, Faculty of Medicine, Universitas Indonesia, Dr. Cipto
Mangunkusumo General Hospital, Jakarta, Indonesia
3
Department of Neurology, Faculty of Medicine, Universitas Padjadjaran, Dr. Hasan
Sadikin General Hospital, Bandung, Indonesia
4
Tuberculosis Working Group, Research Center for Care and Control of Infectious
Disease, Department of Public Health, Faculty of Medicine, Universitas Padjadjaran,
Bandung, Indonesia
5
Oxford University Clinical Research Unit Indonesia, Faculty of Medicine, Universitas
Indonesia, Jakarta, Indonesia
6 3 Soria J, Chiappe A, Gallardo J, et al. Tuberculous meningitis: impact
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine,
University of Oxford, Oxford, UK
7 2021;8:fab345.
Centre for International Health, Division of Health Sciences, University of Otago,
Dunedin, New Zealand
Acknowledgements We thank the hospital management, neurology residents
and field and supportive staff members of the ‘Indonesian Brain Infection Study’
for their support, specifically: Anna Laksmi Sri Wardhani, Cakra Parindra Gasmara,
Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052
BMJ Public Health
Maria Gabriella Sainlia, Anyelir Nielya Mutiara Putri, Arief Susanto, Noerainy Rizky
BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
Siti Rahmawaty, Nury Fitria Dewi and Almira Alifia. The results of this study have
been presented at the International TBM Consortium Meeting 2022 in Oxford, UK.
Contributors GN, DI, RE, KM, SD, ARG, BA, BWL, RLH, RVC and PCH designed the
study. RY, MS, and GN contributed to data collection and curation. SD and BWL
assisted with data curation, and all took responsibility for the integrity of the data.
GN did the analysis and visualised the data with assistance from BWL. GN drafted
the manuscript and acts as guarantor. All authors contributed to data interpretation,
critically revised the manuscript for important intellectual content and all authors
gave final approval for the version to be published.
Funding This project was funded by Universitas Padjadjaran, National Institute Of
Allergy And Infectious Diseases (R01AI145781) and Radboud university medical
centre (R0006111). RLH is supported by the Wellcome Africa Asia Programme
Vietnam (106680/Z/14/Z). ARG, SD, KM, RE, BA, DI, RLH and RVC are also
supported by the National Institute of Health (R01AI165721).
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the
design, or conduct, or reporting, or dissemination plans of this research. Refer to
the Methods section for further details.
Patient consent for publication Not applicable.
Ethics approval This study was approved by the Health Research Ethics
Committees at Faculty of Medicine, Universitas Indonesia (KET-­269/UN2.F1/ETIK/
PPM.00.00/2020). Patients or their family members, if the patient was not fully
conscious or had cognitive impairment, gave informed consent to participate in the
study before taking part.
copyright.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. De-­
identified participant data including the study protocol and data dictionary will
be made available to others upon written requests to the corresponding author
immediately after publication and subject to a written proposal with detailed
description of study objectives, data analysis plan and a signed data sharing
agreement.
Supplemental material This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the
use is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iD
Gerine Nijman http://orcid.org/0000-0002-8716-6286
REFERENCES
1 Dodd PJ, Osman M, Cresswell FV, et al. The global burden of
tuberculous meningitis in adults: A Modelling study. PLOS Glob
Public Health 2021;1:e0000069.
2 Stadelman AM, Ellis J, Samuels THA, et al. Treatment outcomes
in adult tuberculous meningitis: A systematic review and meta-­
analysis. Open Forum Infect Dis 2020;7:ofaa257.
of timing of treatment initiation on mortality. Open Forum Infect Dis
4 Hanson CL, Osberg M, Brown J, et al. Conducting patient-­pathway
analysis to inform programming of tuberculosis services: methods. J
Infect Dis 2017;216(suppl_7):S679–85.
5 Hanson C, Osberg M, Brown J, et al. Finding the missing patients
with tuberculosis: lessons learned from patient-­pathway analyses in
5 countries. J Infect Dis 2017;216(suppl_7):S686–95.
9
BMJ Public Health
6 Lestari BW, McAllister S, Hadisoemarto PF, et al. Patient
pathways and delays to diagnosis and treatment of tuberculosis
in an urban setting in Indonesia. Lancet Reg Health West Pac
2020;5:100059.
7 Seddon JA, Tugume L, Solomons R, et al. The current global
situation for tuberculous meningitis: epidemiology, diagnostics,
treatment and outcomes. Wellcome Open Res 2019;4:167.
8 Ministry of Health of the Republic of Indonesia. Profil Kesehatan
2021. 2022. Available: https://www.kemkes.go.id/downloads/​
resources/download/pusdatin/profil-kesehatan-indonesia/Profil-​
Kesehatan-2021.pdf [Accessed 9 Sep 2022].
9 Surya A, Setyaningsih B, Suryani Nasution H, et al. Quality
tuberculosis care in Indonesia: using patient pathway
analysis to optimize public-­p rivate collaboration. J Infect Dis
2017;216(suppl_7):S724–32.
10 World Health Organization, Regional Office for the Eastern
Mediterranean. Diagnostic and treatment delay in tuberculosis,
. 2006Available: https://apps.who.int/iris/handle/10665/116501
[Accessed 4 Nov 2022].
11 Ministry of Health of the Republic of Indonesia. Online Hospital
Dashboard, The Hospital Information Dashboard is presented in
the form of maps and graphs, Available: https://sirs.kemkes.go.​
id/fo/home/dashboard_rs?id=0 [Accessed 7 Nov 2022].
12 Sheu JJ, Hsu CY, Yuan RY, et al. Clinical characteristics and
treatment delay of cerebral infarction in tuberculous meningitis.
Intern Med J 2012;42:294–300.
13 Huang H-­J , Ren Z-­Z , Dai Y-­N , et al. Old age and hydrocephalus
are associated with poor prognosis in patients with tuberculous
meningitis: A retrospective study in a Chinese adult population.
Medicine (Baltimore) 2017;96:e7370.
14 Ma XP, Li JM, Zhou D, et al. Direct economic burden of patients
with tuberculous meningitis in Western China. Acta Neurol
Scand 2021;144:535–45.
15 Oga-­O menka C, Wakdet L, Menzies D, et al. A qualitative meta-­
synthesis of Facilitators and barriers to tuberculosis diagnosis
and treatment in Nigeria. BMC Public Health 2021;21:279.
16 Marahatta SB, Yadav RK, Giri D, et al. Barriers in the access,
diagnosis and treatment completion for tuberculosis patients in
central and Western Nepal: A qualitative study among patients,
community members and health care workers. PLoS One
2020;15:e0227293.
17 Imran D, Hill PC, McKnight J, et al. Establishing the Cascade of
care for patients with tuberculous meningitis. Wellcome Open
Res 2019;4:177.
10
18 Stallworthy G, Dias HM, Pai M. Quality of tuberculosis care in
BMJ Public Health: first published as 10.1136/bmjph-2023-000052 on 25 November 2023. Downloaded from https://bmjpublichealth.bmj.com on 8 July 2024 by guest. Protected by
the private health sector. J Clin Tuberc Other Mycobact Dis
2020;20:100171.
19 He Y, Han C, Chang K-­F, et al. Total delay in treatment among
tuberculous meningitis patients in China: a retrospective cohort
study. BMC Infect Dis 2017;17:341.
20 Seddon JA, Visser DH, Bartens M, et al. Impact of drug resistance
on clinical outcome in children with tuberculous meningitis. Pediatr
Infect Dis J 2012;31:711–6.
21 Purohit MR, Purohit R, Mustafa T. Patient health seeking and
diagnostic delay in Extrapulmonary tuberculosis: a hospital based
study from central India. Tuberc Res Treat 2019;2019:4840561.
22 Solomons R, Grantham M, Marais BJ, et al. IMCI indicators of
childhood TBM at primary health care level in the Western Cape
province of South Africa. Int J Tuberc Lung Dis 2016;20:1309–13.
23 Imran D, Satiti S, Sugianto P, et al. Barriers to diagnosis and
management of CNS infections in Indonesia. Neurology
2019;92:104–6.
24 Lakoh S, Kamudumuli PS, Penney ROS, et al. Diagnostic capacity
for invasive fungal infections in advanced HIV disease in Africa: a
continent-­wide survey. Lancet Infect Dis 2023;23:598–608.
25 Agustina R, Dartanto T, Sitompul R, et al. Universal health
coverage in Indonesia: concept, progress, and challenges. Lancet
2019;393:75–102.
26 Meherali S, Punjani NS, Mevawala A. Health literacy interventions
to improve health outcomes in Low- and middle-­income countries.
Health Lit Res Pract 2020;4:e251–66.
27 Levy H, Janke A. Health literacy and access to care. J Health
Commun 2016;21 Suppl 1(Suppl):43–50.
28 Glimåker M, Sjölin J, Åkesson S, et al. Lumbar puncture performed
copyright.
promptly or after neuroimaging in acute bacterial meningitis in
adults: A prospective national cohort study evaluating different
guidelines. Clin Infect Dis 2018;66:321–8.
29 Zawedde-­Muyanja S, Reuter A, Tovar MA, et al. Provision of
decentralized TB care services: A detect-­treat-­prevent strategy
for children and adolescents affected by TB. Pathogens
2021;10:1568.
30 Lei X, Liu Q, Escobar E, et al. Public-­private mix for tuberculosis care
and control: a systematic review. Int J Infect Dis 2015;34:20–32.
31 Min J, Ko Y, Kim HW, et al. Increased Healthcare delays in
tuberculosis patients during the first wave of COVID-­19 pandemic
in Korea: A nationwide cross-­sectional study. J Korean Med Sci
2022;37:e20.
Nijman G, et al. BMJ Public Health 2023;1:e000052. doi:10.1136/bmjph-2023-000052